Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GHdeficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 jtg/kg h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH. (J. Clin. Invest.

Objectives. To find out whether insulin‐like growth factor‐I (IGF‐I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. Design. Randomized, crossover study. Setting. University Hospital, Zürich, Switzerland. Subjects. Seven young healthy male subjects. Interventions. Each subject was studied three times at 2‐week intervals, treated with saline 0.9% (S), IGF‐I [8 μg kg−1 h−1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. Main outcome measures. 36 h after the start of treatment, IGF‐I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. Results. Serum levels of IGF‐I were 26.8±7.3 (S), 119.4±11.4 (IGF‐I) (P<0.02) and 58.4±12.9 nmol L−1 (GH) (P<0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/creatinine ratios were all significantly higher after IGF‐I (P<0.02) or GH (P<0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin‐corrected calcium increased only after GH treatment (P<0.05). The free calcitriol index rose from 2.2.±0.5×10−5 (S) to 2.81±0.25×10−5 (IGF‐I) (P<0.03) and 2.45±0.25×10−5 (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P<0.03) but not by IGF‐I as compared to saline 0.9%. Conclusions. (i) Similar to GH, IGF‐I rapidly activates bone turnover. (ii) IGF‐I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF‐I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25‐OHD‐1a‐hydroxylase.

Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2 x 120 micrograms insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean +/- SD) 3.1 +/- 2.6, 1.3 +/- 1.0, 6.3 +/- 1.3, and 4.5 +/- 1.1 mmol/l and decreased to 1.6 +/- 0.8, 0.6 +/- 0.4, 5.0 +/- 1.0, and 3.5 +/- 1.1 mmol/l, respectively, on the last treatment day (p < 0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48 +/- 22 and 32 +/- 18% of control (p < 0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.

To determine whether insulin-like growth factor I (IGF-I) has systemic cardiovascular effects in humans, 60 micrograms/kg IGF-I or saline were injected sc in a cross-over, randomized, double blind fashion into eight healthy male volunteers. Cardiac function and performance were evaluated by echocardiography and exercise test. In parallel, the metabolic effects of IGF-I during exercise were investigated. IGF-I improved cardiac performance with a significant increase in stroke volume and cardiac output by 14% and 18% (P < 0.03 and P < 0.04), respectively. Ejection fraction increased by 9% after IGF-I treatment (P < 0.05). Heart rate was not significantly increased at rest or during exercise. Systolic blood pressure was slightly increased by IGF-I, whereas diastolic blood pressure was slightly decreased, resulting in a continuous increase in the blood pressure amplitude at rest and during exercise, but without reaching statistical significance. Maximal exercise duration and peak oxygen consumption were not changed. Exercise was uneventful, without pathological changes on electrocardiogram records. Glucose levels were unchanged, whereas insulin and C peptide levels were decreased by IGF-I at rest. During exercise, insulin levels were further decreased, and the insulin-sparing effect of exercise resulted in a further enhancement of tissue sensitivity to insulin. GH levels were suppressed by IGF-I treatment at rest, but were still stimulated by exercise. In conclusion, IGF-I has positive inotropic effects in man. Further investigation of the potential role of IGF-I in cardiac conditions such as heart failure appears to be warranted.